TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8+ T-cell homeostasis
TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8+ T-cell homeostasis
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TSC1/mTOR 控制的代谢表观遗传串扰支持 DC 对 CD8 T 细胞稳态的控制
DOI：
10.1371/journal.pbio.3000420
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发表时间：
2019
期刊：
影响因子：
9.8
通讯作者：
Hui Xiao
中科院分区：
文献类型：
--
作者：
Lei Shi;Xia Chen;Aiping Zang;Tiantian Li;Yanxiang Hu;Shixin Ma;Mengdie Lü;Huiyong Yin;Haikun Wang;Xiaoming Zhang;Bei Zhang;Qibin Leng;Jinbo Yang;Hui Xiao
树突状细胞（DC）在T细胞稳态和活化中起关键作用，最近已将代谢编程与DC发育和功能联系起来。然而，与不同的DC功能相对应的代谢基础在很大程度上仍然没有得到解决。在这里，我们展示了一个特殊的代谢-表观遗传耦合机制，由结节性硬化症复合体亚单位1（TSC 1）-雷帕霉素（mTOR）的机制靶点协调，以实现稳态DC功能。DC隔室中Tsc 1的特异性消融（Tsc 1DC-KO）在很大程度上保留了DC发育，但导致幼稚和记忆表型分化簇（CD）8+ T细胞的显著减少，这是一种通过同时消融DC中的mTor或MTOR调节相关蛋白复合物1（Rptor）而完全挽救的缺陷。此外，Tsc 1DC-KO小鼠不能启动有效的抗原特异性CD 8 + T效应子反应，这些反应是包含单核细胞增生李斯特菌和B16黑色素瘤所需的。从机制上讲，我们的数据表明，稳态DC倾向于下调从头脂肪酸合成，并将乙酰辅酶A（乙酰辅酶A）转向组蛋白乙酰化，这是一个由TSC 1-mTOR关键控制的过程。相应地，TSC 1缺乏升高乙酰辅酶A羧化酶1（ACC 1）的表达和脂肪酸的合成，导致受损的表观遗传印记的选择性基因，如主要组织相容性复合体（MHC）-I和白细胞介素（IL）-7。值得注意的是，调节ACC 1活性能够转移细胞溶质乙酰辅酶A用于组蛋白乙酰化，并恢复由TSC 1缺陷损害的基因表达程序。总之，我们的结果揭示了TSC 1-mTOR在稳态DC的代谢编程中对于T细胞稳态的关键作用，并暗示代谢偶联的表观遗传印记作为DC特化的范例。
Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory– phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification..